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Treatment strategies for patients with hepatitis B virus infection coexisting with hepatitis C virus or metabolic dysfunction-associated steatotic liver disease

Chieh Liu1, Yi-Fen Shih2, Chun-Jen Liu3,4,5orcid
Clinical and Molecular Hepatology 2026;32(2):565-579.
Published online: January 9, 2026

1Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan

2Department of Physical Therapy and Assistive Technology, National Yang Ming Chiao Tung University, Taipei, Taiwan

3Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan

4Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan

5Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan

Corresponding author : Chun-Jen Liu Division of Gastroenterology & Hepatology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, 1 Chang-Te Street, Taipei 10002, Taiwan Tel: +886-2-23123456, Fax: +886-2-23825962, E-mail: cjliu@ntu.edu.tw

Editor: Gi-Ae Kim, Kyung Hee University, Korea

• Received: October 28, 2025   • Revised: December 17, 2025   • Accepted: January 2, 2026

Copyright © 2026 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Hepatitis B virus (HBV) remains a major cause of chronic liver diseases, especially in the Asia-Pacific region. In recent decades, coinfection with hepatitis C virus (HCV) and coexistence with metabolic dysfunction-associated steatotic liver disease (MASLD) have emerged as significant clinical concerns among HBV-infected patients. Although global HBV vaccination programs and curative therapies for HCV have led to a marked decline in HBV/HCV coinfection, MASLD is rapidly becoming the predominant comorbidity due to the global surge in metabolic risk factors. HBV/HCV coinfection typically results in more severe liver damage, with unique challenges in antiviral treatment and risk of HBV reactivation post-HCV clearance. In contrast, HBV/MASLD overlap demonstrates complex metabolic-viral interactions that may influence viral replication, hepatitis B surface antigen seroclearance, fibrosis progression, and risk of hepatocellular carcinoma. This review critically compares the epidemiology, clinical outcomes, and management strategies of HBV patients with concurrent HCV or MASLD, while addressing current research gaps and proposing directions for future investigations.
  • Keywords: hepatitis B virus; hepatitis C virus; metabolic dysfunction; steatosis; steatohepatitis
Chronic hepatitis B virus (HBV) infection is still a challenge of global public health, particularly in the Asia-Pacific region [1]. Long-term outcomes of HBV infection can be significantly influenced by concurrent liver conditions, notably hepatitis C virus (HCV) infection and metabolic dysfunction-associated steatotic liver disease (MASLD) [2-8]. These dual pathologies are increasingly recognized as critical modifiers of HBV-related liver disease progression, treatment response, and overall prognosis. Understanding the similarities and differences in how HCV and MASLD impact HBV-infected individuals is essential for guiding appropriate clinical management.
Chronic HBV infection affects over 290 million individuals globally, with the highest burden concentrated in Asian countries [1,9]. In these endemic areas, HBV is often acquired during the perinatal period or early childhood, leading to a high rate of chronic infection [1,9]. While the prevalence of HCV varies regionally, it remains an important coexisting infection in populations at risk for parenteral transmission, for example, people who inject drugs, patients receiving transfusions before blood screening implementation, and individuals with human immunodeficiency virus co-infection [3-5].
Historically, HBV/HCV coinfection has been observed in the Asia-Pacific region before the global implementation of HBV vaccine program and blood product screening [3-5]. In Taiwan and parts of mainland China, earlier studies reported that up to 1% of the population carried both viruses, often due to superinfection with HCV in individuals with hepatitis B surface antigen (HBsAg) carriage [5]. However, in recent years, HBV/HCV coinfection rates have declined due to universal infant HBV vaccination, public health campaigns, and the introduction of direct-acting antiviral (DAA) therapies highly effective for the cure of HCV [5].
In contrast, MASLD has become the most common liver disease in the world, affecting an estimated 25–30% of the global population, with rising incidence across both developing and developed countries [10-32]. This trend is closely linked to the growing prevalence of obesity, sedentary lifestyles, and type 2 diabetes mellitus. In Asia, the burden of MASLD is expanding rapidly. For instance, the prevalence of MASLD in urban Chinese adults rose from approximately 13% in 2003 to over 40% by 2016 [10,15,19-24]. In South Korea, rates have increased from 19% to 27% within a decade [12,17,18].
Among subjects chronically infected with HBV, the co-existence of MASLD is becoming increasingly common, though reported prevalence varies widely from 15% to over 50%, depending on population characteristics and diagnostic methods (Table 1) [15-32]. Interestingly, several studies suggest that chronic infection with HBV may be associated with hepatic steatosis in an inverse way, although this observation remains controversial and may be influenced by metabolic parameters of the host [7,8,33,34]. Nonetheless, with the global rise in metabolic syndrome (MetS), the burden of dual HBV/MASLD is expected to grow, warranting careful attention in clinical management and hepatocellular carcinoma (HCC) surveillance programs [7,8].
Declining prevalence and incidence due to public health policy and the introduction of potent DAA therapy
HBV and HCV coinfection presents complex challenges for diagnosis, treatment planning, and long-term outcome prediction [2-5]. Either cohort or case-control studies have demonstrated that the clinical outcomes are worse in patients with HBV/HCV coinfection compared to those with mono-infection by either virus [2,3]. Specifically, coinfected individuals are at greater risk for accelerated liver fibrosis, decompensation, and development of HCC [2]. These adverse outcomes underscore the need for proactive treatment strategies.
The implementation of global HBV vaccination programs—starting with the World Health Organization’s 1992 recommendation—has significantly reduced new HBV infections and, by extension, the incidence of new HBV/HCV coinfection [1,5]. In parallel, the availability of highly efficacious DAAs for HCV has made viral eradication including HBV/HCV coinfection a feasible goal in nearly all patients [35,36].
What happens during anti-HCV therapy if we only target HCV?
Antiviral therapy in coinfected subjects requires particular caution. Interferon-based regimens such as pegylated interferon (peginterferon) with ribavirin were previously used and showed durable HCV eradication and, in some cases, concurrent reductions in serum HBsAg titers [37-39]. More recently, DAA-based treatments have already become the standard of care for HCV and have demonstrated satisfactory sustained virological response, even in HBV coinfected subjects [35,36]. An unexpected concern is the risk of HBV reactivation (HBVr) following peginterferon- or DAA-induced HCV clearance [35-39].
In subjects with dual liver diseases, the interactions between two etiologies can be quite complex [7]. For example, for subjects coinfected with HBV and HCV, HCV infection has been found to suppress HBV replication [40]. With the advent of potent DAA agents that achieve rapid and sustained eradication of HCV, clinicians began observing an unintended consequence: HBVr [35,36,40].
HBVr typically manifests as a sudden rise in HBV DNA levels, often accompanied by reappearance or increase of HBsAg, and in some cases, biochemical hepatitis flares [41]. The underlying mechanism is thought to involve loss of HCV-mediated immune control, particularly through diminished hepatic interferon signaling [40].
In a multicenter cohort study from Taiwan, HBVr occurred in up to 70% of HBsAg-positive subjects after DAA therapy for HCV, although only 10–15% developed clinically significant hepatitis [35,36]. Most reactivations occurred during or within 12 weeks after the completion of DAA therapy. In severe cases, especially those with underlying cirrhosis, HBVr has led to hepatic decompensation and even liver failure [42,43].
Retrospective studies and case series have also confirmed HBVr risk across various DAA regimens [42,43]. Importantly, HBVr appears to be less common in subjects with isolated anti-HBc (HBsAg-negative) or in those who are inactive HBV carriers with undetectable or low serum HBV DNA [43].
What can we do to prevent HBVr?
Due to the potential for severe liver outcomes, international guidelines—including those by AASLD and EASL—recommend that all subjects scheduled for DAA therapy undergo HBV screening [44,45]. For those with active HBsAg positivity, prophylaxis with nucleos(t)ide analogue (NUC) should be considered starting with DAA therapy and continued for at least 12–24 weeks after its completion [44,45].
A Taiwanese randomized trial demonstrated that entecavir prophylaxis during DAA therapy markedly reduced the risk of HBVr [46]. In patients who received entecavir starting with DAAs, HBVr was reduced from over 60% (no prophylaxis group) to 0%, with no hepatitis flares or liver failure. This finding strongly supports the implementation of antiviral prophylaxis in high-risk subjects.
Surveillance of HCC after eradication of HCV in the HBV/HCV coinfected subjects
HCC surveillance in HBV/HCV-coinfected subjects post-HCV cure is an important concern in clinical practice. Even after HCV eradication, persistent HBsAg or pre-existing fibrosis warrants continued semiannual ultrasound, with or without alpha-fetoprotein monitoring per international society guidance for the development of HCC [47,48].
Lessons we learned from HBV/HCV coinfection
In sum, while DAA therapy revolutionized HCV treatment, clinicians must remain vigilant in subjects with HBV coinfection (Box 1) [7]. HBVr is common, preventable, and may be life-threatening. Prophylactic antiviral therapy and close post-treatment monitoring are critical components of safe and effective management. Unfortunately, HBV screening and prophylactic NUC use during DAA therapy remain inconsistent globally in clinical practice despite international guideline recommendations, and real-world registries show variable HBVr rates [42-45,49].
Another lesson learned from these basic and clinical studies on HBV/HCV coinfection is that there is reciprocal interaction, usually suppressive effect, between two viruses. If the management plan of HBV-related dual liver disease only targets one etiology (HCV in this case) but leaves the HBV infection untreated, HBV may reactivate and potentially lead to severe clinical adverse events, including liver failure. Understanding the risk of HBVr in HBV/HCV coinfected subjects calls for attention to the potential risk of HBVr in other HBV-related dual liver diseases such as HBV/MASLD (Fig. 1).
[Box 1: Insights from HBV and HCV coinfection]
1. HBV-related dual liver disease is common in areas or countries endemic for HBV infection.
2. HBV-related dual liver disease is associated with more severe liver disease than liver disease of either single etiology.
3. Prevention by HBV global vaccination markedly decreases incidence of new HBV-related dual liver disease such as HBV/HCV.
4. Treatment strategy targeting dual etiology is beneficial; clinical outcomes can be improved.
5. Treatment of only one target may lead to reactivation of the other. Monitoring or even proactive prevention of HBVr should be considered.
6. HCC surveillance in HBV/HCV-coinfected subjects post-HCV cure is an important concern in clinical practice. Even after HCV eradication, persistent HBsAg or pre-existing fibrosis can lead to development of HCC.
Coexisting MASLD in subjects with chronic HBV infection is becoming increasingly prevalent (Table 2) [10,13-32]. Importantly, the co-existence of MASLD may influence the disease course and the treatment outcome of HBV infection in complex and sometimes contradictory ways [7,33,34,50-53]. While some studies suggest that steatosis may suppress HBV replication and promote HBsAg seroclearance, others have reported increased risks of liver fibrosis, HCC, and antiviral treatment failure in patients with coexisting metabolic dysfunction [6-8,33,34,50,51]. These discrepancies highlight the need for a better understanding of metabolic-viral interactions in HBV-infected populations.
As MASLD becomes the dominant chronic liver disease in the 21st century, clinicians managing HBV must be equipped to assess, monitor, and address the metabolic contributors to liver injury (Box 2) [7]. Future strategies will likely require an approach targeting both HBV viral suppression and metabolic correction [7]. Details of the above aspects will be reviewed in the following sections.
[Box 2: Unique features and management of dual HBV and MASLD]
1. Dual HBV/MASLD is increasing due to rising rates of obesity and diabetes.
2. Impact of simple steatosis without metabolic derangement seems beneficial in subjects with HBV infection, but the findings remain to be confirmed.
3. Metabolic derangement, particularly the presence of diabetes, accelerates the progression of HBV-related liver fibrosis and hepatocarcinogenesis.
4. Treatment of dual HBV/MASLD needs to target both etiologies.
5. Hepatic steatosis suppresses replication of HBV. Risk of HBVr after correction of metabolic derangement and following improvement of hepatic steatosis is an interesting open question remaining to be evaluated.
Definition of steatotic liver disease and MASLD
Steatotic liver disease (SLD), previously termed as fatty liver disease, is currently the most prevalent liver disorder globally [13,54]. This new nomenclature “SLD” was proposed in 2023 by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver with the aim to avoid stigmatization of the affected subjects [55]. Among SLD, MASLD is defined in patients who have SLD as well as the presence of at least 1 cardiometabolic risk factor [55].
Non-invasive diagnosis of SLD, MASLD, and metabolic dysfunction-associated steatohepatitis
The presence of hepatic steatosis (SLD) can be detected by non-invasive liver imaging study, for example, ultrasonography of the abdomen and computed tomography [55]. The diagnosis of hepatic steatosis in subjects with HBV infection can be made with the help of various clinical models [56-58].
Beyond steatosis, distinguishing metabolic dysfunctionassociated steatohepatitis (MASH) and identification of fibrosis in subjects with HBV infection has also prompted the use of noninvasive algorithms [59,60].
Prevalence of hepatic steatosis in subjects with HBV infection is related to MetS
Several cross-sectional analyses suggest that subjects infected with HBV infection may exhibit lower rates of fatty liver in comparison with the general population or subjects with HCV infection [19,25,28,31,61-65]. The underlying mechanisms accounting for this observation are not fully clarified yet.
To investigate how frequently hepatic steatosis occurs in HBV-infected populations within the Asia–Pacific region, Wong and colleagues conducted a study involving 91 individuals with HBV and 922 healthy controls in Hong Kong [25]. They used magnetic resonance spectroscopy to quantify the content of fat in the liver, and demonstrated that HBV infection was a factor independently associated with a lower likelihood of hepatic steatosis. Only 13.5% of HBV-infected subjects exhibited steatosis as compared to 28.3% among controls (p=0.003). Clinically, individuals with coexisting steatosis are often overweight or obese, older in age, and tend to have hypertension and reduced physical activity levels—traits consistent with metabolic dysfunction [19,25,28,31,62-66].
Cross-sectional studies have consistently shown that hepatic fat accumulation in subjects with chronic HBV infection is more closely associated with features of MetS than with HBV infection itself. For instance, in a Taiwanese health screening cohort of 507 individuals—50 with HBV and 457 without—the presence of fatty liver and insulin resistance was not related to the status of HBV infection [67]. A meta-analysis consisting of 17 studies and 4,100 subjects with HBV infection who had available histological data. It was revealed that the presence of fatty liver was positively correlated with higher body mass index, male gender, higher serum cholesterol level, higher serum triglyceride level, and the presence of prediabetes or type 2 diabetes [65]. Notably, these associations did not extend to HBV infection itself, underscoring the dominant role of metabolic abnormalities in driving steatosis within this patient population.
Effects of hepatic steatosis and metabolic dysfunction on HBV replication and HBsAg seroclearance
One of the most intriguing observations in subjects with chronic HBV infection is the potential inverse correlation between hepatic steatosis and the status of viral replication [8,34]. Several clinical studies have shown that HBV-infected individuals with concurrent steatosis often exhibit lower HBV DNA levels, reduced rates of HBeAg positivity, and higher frequencies of spontaneous HBsAg seroclearance [62,64-67]. For example, in a large Taiwanese cohort of 4084 HBeAg-negative treatment-naïve subjects [51], 887 individuals had coexisting hepatic steatosis. Compared to those without steatosis, these patients exhibited significantly lower serum HBsAg titer and lower serum HBV DNA titer. Over a median follow-up of five years, hepatic steatosis was found to be associated with a higher chance of achieving HBsAg seroclearance (the adjusted hazard ratio [aHR] being 1.43). Furthermore, the presence of individual metabolic dysfunctions showed a cumulative and additive effect on enhancing HBsAg clearance. Patients with hepatic steatosis also demonstrated a greater likelihood of HBsAg seroconversion (aHR 1.37) compared to their counterparts without steatosis. These results remained robust across multiple sensitivity analyses and persisted even after adjusting for virological and clinical parameters through inverse probability of treatment weighting. Collectively, these findings suggest that metabolic factors may not only influence disease progression but also facilitate favorable immunological outcomes in HBV infection including reduction in serum HBsAg level and even HBsAg seroclearance.
The mechanisms underlying this phenomenon remain to be investigated [68-71]. In vitro studies suggest that hepatocyte lipid accumulation may impair HBV replication via induction of endoplasmic reticulum (ER) stress, autophagy disruption, or cytokine signaling alterations. Additionally, adipokines such as adiponectin and leptin may play immunomodulatory roles that influence HBV viral dynamics.
Animal models support these findings. In HBV-transgenic mice fed with high-fat diets, investigators observed a marked suppression of viral markers, including reduction in serum HBsAg and HBsAg levels [72,73]. Similarly, in cellular models, lipid accumulation inhibited secretion of viral particles [74]. These findings propose a theoretical model in which metabolic stress interferes with HBV persistence mechanisms.
Impact of MetS on HBV-related fibrosis progression and hepatocarcinogenesis
The contribution of MetS to HBV-related liver disease progression has been increasingly recognized. In a longitudinal study involving 663 untreated HBV-infected individuals, Wong et al. [75] assessed the dynamic changes in MetS and their impact on hepatic fibrosis over a two-year period. Liver stiffness was measured at baseline and follow-up using transient elastography. During the observation window, the prevalence of MetS rose from 12% to 21%, with 13% of subjects developing new-onset MetS and 3% experiencing resolution. Notably, 16% exhibited fibrosis progression. Multivariate analysis identified coincidental MetS as an independent risk factor for fibrotic advancement, with an adjusted odds ratio of 2. These findings support the role of metabolic disturbances in exacerbating liver damage in HBV-infected individuals.
MetS encompasses five key elements—diabetes, obesity, hypertriglyceridemia, hypercholesterolemia, and hypertension—but whether specific type or cumulative number of these abnormalities has a greater impact on hepatocarcinogenesis in subjects with chronic hepatitis B is still an open question. In a Taiwanese cohort of 1,690 men with HBV infection followed over a median period of 19 years [76], individuals presenting with ≥3 metabolic abnormalities had significantly higher risks of HCC (hazard ratio 2.32) and liver-related mortality (hazard ratio 2.72). Similarly, a Canadian biopsy-based cohort of 1,850 CHB subjects revealed that those with MetS had a heightened risk of liver complications, especially among those with multiple concurrent metabolic comorbidities [77]. Reinforcing these findings, a recent hospital-based study involving over 10,000 untreated CHB subjects in Taiwan found a clear dose-dependent relationship between the number of metabolic dysfunctions and the incidence of HCC, with type 2 diabetes mellitus emerging as the most prominent individual risk factor [33]. Korean nationwide study also demonstrated that metabolic risk factors independently increased risk of HCC [78].
Interestingly, some investigations have demonstrated an inverse relationship between serum lipid levels and the risk of HCC. Elevated total cholesterol level, triglyceride level, and low density lipoprotein level were linked to a lower likelihood of developing HCC in both the general population and HBV-infected individuals [79]. However, these observations require confirmation through prospective studies and deeper mechanistic exploration to better understand this paradox. Cohort studies also demonstrated contradictory findings that use of statins was associated with lower HCC incidence in CHB patients [80-82].
Overall, HBV/MASLD is associated with a higher risk of hepatocarcinogenesis. Thus, HCC surveillance in HBV subjects with MASLD is recommended. However, in non-cirrhotic or younger (for example, those <40 years of age) populations, whether routine surveillance of HCC is costeffective remains uncertain and needs to be investigated in future cohort studies [83-85].
Intriguing role of simple hepatic steatosis in HBV-related liver disease progression
Co-existing hepatic steatosis and MetS are common among subjects infected with HBV, yet their individual and combined contributions to HCC risk remain contentious. In a recent retrospective study collecting more than 10,000 treatment-naïve HBV patients, hepatic steatosis—observed in 21% of the cohort—was associated with favorable virological and biochemical profiles, such as lower HBeAg positivity rates, reduced serum HBV DNA levels, and a decreased Fibrosis-4 (FIB-4) index [33]. During a median 5.1-year follow-up, hepatic steatosis emerged as an independent factor associated with a 60% reduction in HCC risk.
Based on the same cohort, similar beneficial impact of simple steatosis was observed regarding the risk of allcause mortality and cause-specific mortality [50]. After a median follow-up of 9.1 years, subjects with simple steatosis had a lower risk of mortality (hazard ratio 0.62) than those without MASLD. Among non-cirrhotic subjects with HBV infection, hepatic steatosis was associated with a lower risk of developing liver cirrhosis (aHR 0.57 within 5 years) and cirrhosis-related complications (aHR 0.45) [6]. Notably, among individuals with SLD, the risk of developing cirrhosis was higher in subjects with co-existing metabolic dysfunction in comparison to those without metabolic dysfunction.
Conversely, other studies have suggested adverse implications of steatosis. A Hong Kong-based cohort of 270 HBV-infected subjects who received liver biopsy found that 40% had biopsy-proven steatosis at baseline [25]. These patients frequently exhibited features of metabolic dysfunction, advanced liver disease including cirrhosis, and genetic susceptibility linked to the PNPLA3 rs738409 CG/GG variant. Steatosis in this group independently increased HCC risk by over seven-fold during a 6.5-year follow-up. However, the presence of cirrhosis in over a quarter of these individuals at baseline limits generalizability to broader clinical settings.
Meta-analyses have echoed these mixed findings [14,86-88]. While some pooled analyses showed no significant link between hepatic steatosis and fibrosis or cirrhosis in CHB [86], others reported a paradoxical inverse association between steatosis and HCC development [87]. One individual patient data meta-analysis even found reduced risks of HCC, cirrhosis, and mortality in CHB patients with hepatic steatosis, along with higher rates of HBsAg seroclearance [88]. These discrepancies likely reflect heterogeneity in disease severity across cohorts and call for more refined studies with clearly defined clinical subtypes.
These complex dynamics underscore the need for careful risk stratification among subjects with dual HBV/MASLD, into those with versus those without coexisting MetS. Data from Taiwan’s cohorts clearly revealed that the presence of simple hepatic steatosis without metabolic derangement may be associated with favorable clinical and virologic outcomes [6,8,33,50,51]. However, the presence of any metabolic derangement, especially type 2 diabetes, contributes to the development of HBV-related liver cirrhosis, HCC, and liverrelated mortality. Overall, although reduced viral replication may confer some benefits, this must be balanced against the detrimental hepatic effects of metabolic dysfunction [8,89].
Impact summary of MASLD and metabolic disorders on HBV-related events
In summary, the clinical significance of SLD and associated metabolic disorders on HBsAg seroclearance, development of liver cirrhosis, HCC, liver-related mortality and overall mortality had been investigated in our hospital-based cohort from Taiwan [6,8,33,50,51] and demonstrated in a recent individual patient data meta-analysis [14]. In brief, the presence of simple hepatic steatosis without any metabolic derangement seems beneficial regarding the control of viral replication, achievements of functional care (HBsAg seroclearance), and prevention of HBV-related liver disease progression including the development of liver cirrhosis and HCC. In contrast, concurrent metabolic derangement, particularly the presence of type 2 diabetes mellitus, may accelerate the progression of liver diseases and lead to a higher rate of HCC development. Our findings from these serial studies and other consistent or contradictory data are summarized in Table 3. Notably, the data regarding the impact of steatosis on fibrosis progression or HCC development remains controversial and awaits further investigation.
Integrative approaches to target both HBV and MASLD
Dual HBV/MASLD is associated with more adverse clinical outcomes than single HBV or MASLD. Thus, ideal treatment strategies should focus on both liver disease etiologies. However, management of CHB in subjects with coexisting MASLD poses unique challenges [89]. Traditionally, treatment of HBV has focused on long-term viral suppression by using NUCs. In the setting of SLD with versus without concurrent metabolic dysfunction, additional therapeutic considerations are warranted [90,91]. Notably, the impact of MASLD improvement through lifestyle change as well as new agents against MASH on the clinical manifestations of chronic HBV infection including the treatment outcomes awaits further studies. As for the management of MASLD, lifestyle intervention is the key. Similarly, the influence of co-existing HBV infection on the outcomes of MASLD/MASH interventions needs more investigations. These mutual interaction data will influence the development of future strategies for subjects with dual HBV/MASLD.
Influence of hepatic steatosis on the treatment outcomes of chronic hepatitis B
Current treatment recommendations for chronic hepatitis B remain the same in subjects with concurrent MASLD. One meta-analysis suggests that the presence of MASLD might potentially benefit the virologic efficacy of NUCs or interferon-based therapy [91,92]. However, other studies have reported that the rates of HBV DNA suppression and HBeAg seroconversion between subjects with versus without hepatic steatosis were comparable [93,94]. Besides, the risk of HCC is higher in the presence of MASLD [33]. Therefore, the impact of simple hepatic steatosis without metabolic derangement versus MASLD with metabolic derangement on the clinical and treatment outcomes of HBVinfected subjects should be addressed first using cohorts with clear clinical phenotypes of dual HBV and MASLD in the future. The strategies to manage anti-HBV treated subjects with concurrent SLD or MASLD can then be made accordingly.
Potential goals and benefits of improving hepatic steatosis in HBV-infected subjects
Steatosis has been found to negatively influence the long-term treatment outcomes by impairing fibrosis regression, as shown in studies where overweight subjects had lower rates of fibrosis improvement despite adequate viral suppression [95]. Therefore, clinicians are encouraged to address modifiable metabolic risk factors as part of routine HBV care [90]. Lifestyle interventions—including weight reduction, dietary optimization, and increased physical activity—can improve insulin sensitivity and potentially reduce hepatic steatosis. Observational studies indicate that these interventions may enhance the benefits of antiviral therapy by facilitating fibrosis regression and lowering HCC risk [96]. Potential benefits of reducing steatosis in the liver include the followings:
• Reduced fibrosis and cancer risk - Lifestyle interventions such as weight reduction (5–10%), dietary changes, and regular exercise decrease steatosis and hepatic inflammation, with the potential of slowing HBV-related fibrosis progression and lowering HCC risk.
• Improved insulin resistance - Insulin resistance drives both MASLD progression and HBV-related carcinogenesis. Correction of metabolic abnormalities reduces systemic and hepatic inflammatory milieu, improving long-term outcomes.
• Better response to antiviral therapy - NUCs (e.g., entecavir, tenofovir) effectively suppress HBV replication. When combined with metabolic improvement, patients might have a higher chance of obtaining normalization of liver enzyme levels and greater histological recovery.
Management principles of MASLD in subjects with chronic viral hepatitis B (Table 4)
Pharmacologic treatment of MASLD in the context of HBV remains investigational (Table 4). Agents such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors have shown promise in improving steatosis and metabolic parameters in MASLD [97], but their safety and efficacy in HBV-infected individuals require further validation. Until more evidence emerges, lifestyle modification remains the cornerstone of metabolic intervention in HBV/MASLD comorbidity. Recently, the efficacy of structured lifestyle programs such as the Diabetes Prevention Program has been emphasized regarding the mitigation of HBV-related liver disease progression [98].
Regular surveillance for HCC and fibrosis progression is particularly important in HBV/MASLD subjects, even in those with well-controlled HBV. Non-invasive tests such as FibroScan®, FIB-4, or serum biomarkers should be incorporated into longitudinal care. For individuals with diabetes, obesity, or MetS, more frequent imaging and biochemical monitoring may be necessary.
Despite growing insights into the coexistence of HBV infection and MASLD, several key challenges remain. First, the complex interplay between HBV, MetS, and hepatic steatosis warrants deeper mechanistic investigation using robust in vitro and animal models [52]. Understanding the molecular basis of these interactions may reveal novel therapeutic targets. Second, both host-related and viral factors that contribute to variability in clinical outcomes need further clarification. Identification of biomarkers predictive of disease progression or treatment response could facilitate personalized management. Third, clinical trials are essential to determine whether targeted interventions—such as metabolic modulation through lifestyle changes or pharmacologic agents—can positively alter the disease trajectory in subjects with chronic HBV infection. Fourth, for subjects with HBV infection and simple hepatic steatosis without any metabolic derangement, whether the steatosis should be treated or not remains an interesting question to be investigated. Fifth, during the correction of metabolic derangement in subjects with HBV infection, what happens to HBV replication? Will HBVr occur? All these issues await future long-term follow-up studies to clarify. Overall, integrating the detection and management of metabolic dysfunction into HBV care pathways may be a crucial step toward improving long-term outcomes in this growing patient population.

Authors’ Contribution

Chapter design: Liu C, Shih YF, Liu CJ. Analysis and interpretation of papers: Liu C, Shih YF, Liu CJ. Drafting of the chapter manuscript: Liu C, Shih YF. Critical revision of the chapter: Liu CJ.

Acknowledgements

The work was supported by grants from the National Taiwan University Hospital; and the Ministry of Science and Technology (NSTC 112-2314-B-002-205-MY3, NSTC 113-2314-B-002-241), Executive Yuan, Taiwan.

The authors have used AI-assisted technologies (ChatGPT 5.0) in the preparation of this manuscript.

Conflicts of Interest

The authors have no conflicts to disclose.

Figure 1.
Management strategies in subjects with HBV/HCV coinfection and subjects with HBV/MASLD. The distinct interactions and clinical implications of dual HBV/HCV and HBV/MASLD are illustrated. Briefly, HBV and HCV exhibit mutual viral inhibition, and HBV may reactivate after successful HCV eradication. In contrast, MASLD may promote HBsAg loss but accompanying metabolic syndrome accelerates liver disease severity and fibrosis progression. Both dual etiologies require shared management strategies including treatment of both liver etiologies and regular HCC surveillance. HBV, hepatitis B virus; HCV, hepatitis C virus; MASLD, metabolic dysfunction-associated steatotic liver disease; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma.
cmh-2025-1227f1.jpg
Table 1.
Prevalence of metabolic dysfunction-associated steatotic liver disease in HBsAg-positive subjects in the Asia-Pacific region
Table 1.
Reference Period (HBsAg carrier no.) Co-existing SLD (%) Diagnostic method
Taiwan (Lin et al., 2007) [16] 2004–2005 (817) 34 Ultrasound
South Korea (Yun et al., 2009) [17] 2005–2006 (86) 51 Histology
South Korea (Lee et al., 2019) [18] 2007–2015 (321) 22 Histology
Mainland China (Peng et al., 2008) [19] 2002–2006 (153) 27 Histology
Mainland China (Shi et al., 2008) [20] 2005–2007 (1,915) 14 Histology
Mainland China (Zheng et al., 2010) [21] 2005–2009 (204) 52 Histology
Mainland China (Wang et al., 2014) [22] 2002–2011 (3,212) 17 Histology
Mainland China (Huang et al., 2020) [23] 2016–2018 (2,110) 30 Ultrasound
Mainland China (Lv et al., 2021) [24] 2013–2017 (5,680) 31 Transient elastography
Hong Kong (Wong et al., 2012) [25] 2008–2010 (75) 14 1H-MRS
Hong Kong (Chan et al., 2017) [26] 2006–2009 (270) 40 Histology
Hong Kong (Seto et al., 2018) [27] 2015–2016 (1,606) 41 Transient elastography
India (Rastogi et al., 2011) [28] NA (350) 34 Histology
Malaysia (Wong et al., 2020) [29] 2013–2017 (614) 48 Transient elastography
Thailand (Charatcharoenwitthaya et al., 2017) [30] 2010–2013 (256) 38 Histology
Turkey (Altlparmak et al., 2005) [31] 1997–2002 (164) 39 Histology
Iran (Poortahmasebi et al., 2014) [32] 2010–2011 (160) 44 Histology

Adapted after the article of Yang and Wei (Liver Int 2022;42:1981-1990). [15]

HBsAg, hepatitis B surface antigen; SLD, steatotic liver disease; 1H-MRS, proton-magnetic resonance spectroscopy; NA, not available.

Table 2.
Comparison between dual HBV/HCV and dual HBV/MASLD
Table 2.
Parameter HBV/HCV HBV+MASLD
Prevalence trend Decreasing due to HBV vaccination and HCV DAA therapy Increasing due to rising rates of obesity and diabetes mellitus
Interactions HCV suppresses HBV replication; risk of HBVr after HCV cure MASLD may attenuate HBV replication
Fibrosis progression Accelerated, particularly with high HBV viral loads Variable; more influenced by metabolic factors; beneficial impact of simple steatosis remains to be confirmed
HCC risk High; synergistic oncogenic potential Controversial; metabolic factors increase HCC risk; but simple steatosis is associated with a lower HCC risk
Treatment considerations Peginterferon plus ribavirin combination therapy is beneficial for both HBV and HCV; requires monitoring and/or prophylaxis for HBVr during HCV DAA therapy Standard HBV treatment applies; metabolic correction essential for optimal liver health
Surveillance strategy Close monitoring post-DAA therapy for HBVr and HCC Monitoring of HCC; monitoring of HBVr post correction of metabolic derangement?
Public health impact Controlled with mass vaccination and antiviral therapy Emerging concern needing integrated metabolic care models

HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; DAA, direct-acting antiviral; HBVr, HBV reactivation.

Table 3.
Impact of SLD on the HBV replication and outcome of HBV infection
Table 3.
SLD without metabolic derangement SLD with metabolic derangements
Viral parameters
 HBV replication Lower serum HBsAg titer; lower serum HBV DNA level
 Rate of HBsAg seroclearance Increased; higher in the presence of metabolic derangement
Clinical outcomes
 Newly developed liver cirrhosis Lower risk Higher risk
 Risk of HCC Lower Higher
 Risk of all-cause mortality Lower Higher
 Risk of liver-specific mortality Lower Higher
Treatment outcomes
 NUC Controversial
 Pegylated IFN Controversial

SLD, steatotic liver disease; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; NUC, nucleos(t) ide analogue; IFN, interferon.

Table 4.
Management strategies for concurrent MASLD in subjects with HBV
Table 4.
Potential strategy Rationale
Metabolic modifiers Metformin improves insulin sensitivity and might reduce HCC risk
GLP-1 receptor agonists and SGLT2 inhibitors show promise in reducing steatosis and improving metabolic parameters, though data in HBV remain limited
Statins lower cardiovascular risk and might confer protective effects against HCC
Mechanistic insights Insulin resistance: Increases free fatty acid influx into hepatocytes, aggravating oxidative stress
Oxidative stress and cytokines: TNF-alpha and IL-6 upregulation accelerate hepatic injury
HBV–lipid metabolism interactions: HBV might modulate lipid pathways, but data remain controversial; MetS likely dominates metabolic dysregulation
Clinical management strategies Integrated care: Combine antiviral therapy with MetS-directed interventions
Lifestyle modifications: Weight reduction (≥7% body weight), Mediterranean-style diet, and regular physical activity
Pharmacologic options: Judicious use of antidiabetic and lipid-lowering agents with potential hepatoprotective benefits
Enhanced surveillance: Standard HBV HCC screening (ultrasound±AFP every 6 months) should be strictly enforced; intensified surveillance may be warranted in subjects with dual HBV and MASLD
Future perspectives Development of risk calculators incorporating viral and metabolic factors
Clinical trials assessing novel metabolic therapies in HBV cohorts
Asia-Pacific–specific guidelines integrating MASLD/MASH into HBV management

MASLD, metabolic-dysfunction-associated steatotic liver disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; GLP-1 glucagon-like peptide 1; SGLT2, sodium-glucose cotransporter 2; TNF-alpha, tumor necrosis factor-alpha; IL, interleukin; MetS, metabolic syndrome; AFP, alpha fetoprotein; MASH, metabolic dysfunction-associated steatohepatitis.

aHR

adjusted hazard ratio

DAA

direct-acting antiviral

FIB-4

Fibrosis-4

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

HBVr

HBV reactivation

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

MASH

metabolic dysfunction-associated steatohepatitis

MASLD

metabolic dysfunction-associated steatotic liver disease

MetS

metabolic syndrome

NUC

nucleos(t)ide analogue

SLD

steatotic liver disease
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Treatment strategies for patients with hepatitis B virus infection coexisting with hepatitis C virus or metabolic dysfunction-associated steatotic liver disease
Clin Mol Hepatol. 2026;32(2):565-579.   Published online January 9, 2026
DOI: https://doi.org/10.3350/cmh.2025.1227
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Treatment strategies for patients with hepatitis B virus infection coexisting with hepatitis C virus or metabolic dysfunction-associated steatotic liver disease
Clin Mol Hepatol. 2026;32(2):565-579.   Published online January 9, 2026
DOI: https://doi.org/10.3350/cmh.2025.1227
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Treatment strategies for patients with hepatitis B virus infection coexisting with hepatitis C virus or metabolic dysfunction-associated steatotic liver disease
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Figure 1. Management strategies in subjects with HBV/HCV coinfection and subjects with HBV/MASLD. The distinct interactions and clinical implications of dual HBV/HCV and HBV/MASLD are illustrated. Briefly, HBV and HCV exhibit mutual viral inhibition, and HBV may reactivate after successful HCV eradication. In contrast, MASLD may promote HBsAg loss but accompanying metabolic syndrome accelerates liver disease severity and fibrosis progression. Both dual etiologies require shared management strategies including treatment of both liver etiologies and regular HCC surveillance. HBV, hepatitis B virus; HCV, hepatitis C virus; MASLD, metabolic dysfunction-associated steatotic liver disease; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma.

Figure 1.

Treatment strategies for patients with hepatitis B virus infection coexisting with hepatitis C virus or metabolic dysfunction-associated steatotic liver disease
Reference Period (HBsAg carrier no.) Co-existing SLD (%) Diagnostic method
Taiwan (Lin et al., 2007) [16] 2004–2005 (817) 34 Ultrasound
South Korea (Yun et al., 2009) [17] 2005–2006 (86) 51 Histology
South Korea (Lee et al., 2019) [18] 2007–2015 (321) 22 Histology
Mainland China (Peng et al., 2008) [19] 2002–2006 (153) 27 Histology
Mainland China (Shi et al., 2008) [20] 2005–2007 (1,915) 14 Histology
Mainland China (Zheng et al., 2010) [21] 2005–2009 (204) 52 Histology
Mainland China (Wang et al., 2014) [22] 2002–2011 (3,212) 17 Histology
Mainland China (Huang et al., 2020) [23] 2016–2018 (2,110) 30 Ultrasound
Mainland China (Lv et al., 2021) [24] 2013–2017 (5,680) 31 Transient elastography
Hong Kong (Wong et al., 2012) [25] 2008–2010 (75) 14 1H-MRS
Hong Kong (Chan et al., 2017) [26] 2006–2009 (270) 40 Histology
Hong Kong (Seto et al., 2018) [27] 2015–2016 (1,606) 41 Transient elastography
India (Rastogi et al., 2011) [28] NA (350) 34 Histology
Malaysia (Wong et al., 2020) [29] 2013–2017 (614) 48 Transient elastography
Thailand (Charatcharoenwitthaya et al., 2017) [30] 2010–2013 (256) 38 Histology
Turkey (Altlparmak et al., 2005) [31] 1997–2002 (164) 39 Histology
Iran (Poortahmasebi et al., 2014) [32] 2010–2011 (160) 44 Histology
Parameter HBV/HCV HBV+MASLD
Prevalence trend Decreasing due to HBV vaccination and HCV DAA therapy Increasing due to rising rates of obesity and diabetes mellitus
Interactions HCV suppresses HBV replication; risk of HBVr after HCV cure MASLD may attenuate HBV replication
Fibrosis progression Accelerated, particularly with high HBV viral loads Variable; more influenced by metabolic factors; beneficial impact of simple steatosis remains to be confirmed
HCC risk High; synergistic oncogenic potential Controversial; metabolic factors increase HCC risk; but simple steatosis is associated with a lower HCC risk
Treatment considerations Peginterferon plus ribavirin combination therapy is beneficial for both HBV and HCV; requires monitoring and/or prophylaxis for HBVr during HCV DAA therapy Standard HBV treatment applies; metabolic correction essential for optimal liver health
Surveillance strategy Close monitoring post-DAA therapy for HBVr and HCC Monitoring of HCC; monitoring of HBVr post correction of metabolic derangement?
Public health impact Controlled with mass vaccination and antiviral therapy Emerging concern needing integrated metabolic care models
SLD without metabolic derangement SLD with metabolic derangements
Viral parameters
 HBV replication Lower serum HBsAg titer; lower serum HBV DNA level
 Rate of HBsAg seroclearance Increased; higher in the presence of metabolic derangement
Clinical outcomes
 Newly developed liver cirrhosis Lower risk Higher risk
 Risk of HCC Lower Higher
 Risk of all-cause mortality Lower Higher
 Risk of liver-specific mortality Lower Higher
Treatment outcomes
 NUC Controversial
 Pegylated IFN Controversial
Potential strategy Rationale
Metabolic modifiers Metformin improves insulin sensitivity and might reduce HCC risk
GLP-1 receptor agonists and SGLT2 inhibitors show promise in reducing steatosis and improving metabolic parameters, though data in HBV remain limited
Statins lower cardiovascular risk and might confer protective effects against HCC
Mechanistic insights Insulin resistance: Increases free fatty acid influx into hepatocytes, aggravating oxidative stress
Oxidative stress and cytokines: TNF-alpha and IL-6 upregulation accelerate hepatic injury
HBV–lipid metabolism interactions: HBV might modulate lipid pathways, but data remain controversial; MetS likely dominates metabolic dysregulation
Clinical management strategies Integrated care: Combine antiviral therapy with MetS-directed interventions
Lifestyle modifications: Weight reduction (≥7% body weight), Mediterranean-style diet, and regular physical activity
Pharmacologic options: Judicious use of antidiabetic and lipid-lowering agents with potential hepatoprotective benefits
Enhanced surveillance: Standard HBV HCC screening (ultrasound±AFP every 6 months) should be strictly enforced; intensified surveillance may be warranted in subjects with dual HBV and MASLD
Future perspectives Development of risk calculators incorporating viral and metabolic factors
Clinical trials assessing novel metabolic therapies in HBV cohorts
Asia-Pacific–specific guidelines integrating MASLD/MASH into HBV management
Table 1. Prevalence of metabolic dysfunction-associated steatotic liver disease in HBsAg-positive subjects in the Asia-Pacific region

Adapted after the article of Yang and Wei (Liver Int 2022;42:1981-1990). [15]

HBsAg, hepatitis B surface antigen; SLD, steatotic liver disease; 1H-MRS, proton-magnetic resonance spectroscopy; NA, not available.

Table 2. Comparison between dual HBV/HCV and dual HBV/MASLD

HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; DAA, direct-acting antiviral; HBVr, HBV reactivation.

Table 3. Impact of SLD on the HBV replication and outcome of HBV infection

SLD, steatotic liver disease; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; NUC, nucleos(t) ide analogue; IFN, interferon.

Table 4. Management strategies for concurrent MASLD in subjects with HBV

MASLD, metabolic-dysfunction-associated steatotic liver disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; GLP-1 glucagon-like peptide 1; SGLT2, sodium-glucose cotransporter 2; TNF-alpha, tumor necrosis factor-alpha; IL, interleukin; MetS, metabolic syndrome; AFP, alpha fetoprotein; MASH, metabolic dysfunction-associated steatohepatitis.

Table 1.

Table 2.

Table 3.

Table 4.

Clin Mol Hepatol : Clinical and Molecular Hepatology
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